Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder of poorly understood etiology that affects an estimated 1.5 million Americans. Neuropsychiatric SLE (NPSLE) is a common subtype [1, 2] that has been described as “the least understood, yet perhaps the most prevalent manifestation of lupus” [3]. In NPSLE, a CNS with a compromised blood brain barrier is targeted by autoimmune antibodies [4]. Disease manifestations include cognitive dysfunction and seizure activity [3, 5]. In SLE patients, seizures are the second most frequent neurological feature (after headaches) and occur with a frequency of 25-42% [6, 7]. In healthy subjects, seizures occur in 0.5-1% of cases. In patients with SLE, there are no indicators available for predisposition to NPSLE, seizures in particular. Seizures in SLE patients may be focal or generalized. Generalized tonic-clonic seizures occur much more frequently than other types of epilepsy. They are associated with active SLE disease, whereas focal seizures may recur at any time irrespective of disease activity. The risk of seizures is increased in those patients with higher disease activity [6].
Autoantibodies of lupus patients are often reactive to nucleic acids or their binding proteins (8). Regulatory RNAs play important roles in the control of gene expression in eukaryotic cells [9, 10]. Regulatory brain specific cytoplasmic RNAs (BC RNAs) are translational repressors that have been implicated in the regulation of protein synthesis in mammalian nerve cells [11-13]. BC RNAs are small RNAs (150-200 nt, i.e. distinct from miRNAs) that function by interacting with components of the eukaryotic translational machinery [11-13]. Specifically, primate BC1 RNA targets the helicase activity of eukaryotic initiation factor 4A (eIF4A), an abundant canonical translation factor that is required for efficient initiation of mRNAs by unwinding higher-order structure content in their 5′ untranslated regions (UTRs) [13]. BC RNA transport from the soma to synaptic-dendritic domains is mediated by heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2). Transport factors such as hnRNP A2 recognize RNA motif structures known as dendritic targeting elements or (DTEs) [13]. hnRNP A2 recognizes a DTE, in the form of a noncanonical GA motif, that is located in the BC RNA 5′ region. Mice lacking BC1 RNA-mediated translational control are susceptible to hyperexcitability and seizures.
50-90% of lupus patients will develop neuropsychiatric SLE during their lifetimes. Currently, no indicators are available to identify patients that will manifest this pathology. In view of these limitations, improved methods to follow the evolution of the disease through different stages (manifestation, remission, flares) and to identify patients with a predisposition for this condition are clearly needed.